Origin of Chiral Induction in Radical Reactions with the Diastereoisomers (5R)- and (5S)-5-l-Menthyloxyfuran-2[5H]-one

Article abstract of DOI:10.1021/jo030292x

Acetalization of 5-hydroxyfuran-2[5H]-one with l-menthol yields (5R)-(1) and (5S)-5-l-menthyloxyfuran-2[5H]-one (2) in equal amounts. The diastereomer 1 crystallizes preferentially. For the first time, the isolation of pure diastereoisomer 2 is reported. Different diastereoselectivities were observed in the radical tandem reaction of 1 and 2 with N,N-dimethylaniline. The privileged conformations in solution of the substrates and the products of the radical reaction were then determined, and X-ray crystal structure analyses were carried out on the reaction products. The different stereoselectivities in both cases are explained by different orientations of the menthyloxy substituent.

Full text of DOI:10.1021/jo030292x

Or igin of Ch ir a l In d u ction in Ra d ica l Rea ction s w ith th e
Dia ster eoisom er s (5R)- a n d (5S)-5-l-Men th yloxyfu r a n -2[5H]-on e
Sinisˇa Marinkovic´,† Ce´dric Brule´,† Norbert Hoffmann,*,† Elise Prost,‡
J ean-Marc Nuzillard,‡ and Ve´ronique Bulach§
Laboratoire des Re´actions Se´lectives et Applications, UMR (6519) CNRS et Universite´ de Reims
Champagne-Ardenne, UFR Sciences, B.P. 1039, F-51687 Reims, Cedex 2, France, Laboratoire d’Isolement,
Structure, Transformations et Synthe`se de Substances Naturelles, UMR (6013) CNRS et Universite´ de
Reims Champagne-Ardenne, UFR Sciences, B.P. 1039, F-51687 Reims, Cedex 2, France, and Laboratoire
de Chimie de Coordination Organique (UMR 7513 CNRS) Institut Le Bel, Universite´ Louis Pasteur,
4 rue Blaise Pascal, F-67070 Strasbourg, Cedex, France
norbert.hoffmann@univ-reims.fr
Received September 18, 2003
Acetalization of 5-hydroxyfuran-2[5H]-one with l-menthol yields (5R)- (1) and (5S)-5-l-menthyloxy-
furan-2[5H]-one (2) in equal amounts. The diastereomer 1 crystallizes preferentially. For the first
time, the isolation of pure diastereoisomer 2 is reported. Different diastereoselectivities were
observed in the radical tandem reaction of 1 and 2 with N,N-dimethylaniline. The privileged
conformations in solution of the substrates and the products of the radical reaction were then
determined, and X-ray crystal structure analyses were carried out on the reaction products. The
different stereoselectivities in both cases are explained by different orientations of the menthyloxy
substituent.
SCHEME 1
In tr od u ction
Although catalytic methods1-3 of chiral induction are
actually intensively investigated, stoichiometric methods
remain important especially because these strategies
reveal to be very flexible (for a review of different chiral
auxiliaries, see ref 1). About 25 years ago, the homochiral
(5R)-5-l-menthyloxyfuran-2[5H]-one (1) (Scheme 1) was
synthesized with the aim of application to asymmetric
synthesis of chiral insecticides.4 A large number of
functional groups are localized on a minimal number of
carbon atoms. Menthyloxyfuran-2[5H]-one is also a par-
ticular interesting chiral synthon since the two enanti-
omers are equally well available. The enantiomer 1
possessing the configuration R at the chiral acetal center
in position 5 is obtained by crystallization when (-)- or
l-menthol is used as chiral alcohol component while en t-1
is obtained in the same way when (+)- or d-menthol is
used.5,6 The potential of 5-menthyloxyfuran-2[5H]-one for
a wider application to organic syntheses was recognized
sometime later.7
† Laboratoire des Re´actions Se´lectives et Applications.
‡ Laboratoire d’Isolement, Structure, Transformations et Synthe`se
de Substances Naturelles.
§ Laboratoire de Chimie de Coordination Organique.
(1) Seyden-Penne, J . Synthe`se et catalyse ayme´triques; CNRS Edi-
tions: Paris, 1994.
A large number of ground-state reactions such as
Michael reactions,5,8 cyclopropanations,9,10 Diels-Alder
(2) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J .
Wiley & Sons: New York, 1994. (b) Wong, C. H.; Whitesides, G. M.
Enzymes in Synthetic Organic Chemistry; Pergamon: New York, 1994.
(c) Ojima, I., Ed. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley
VCH: New York, 2000. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (e) Girard, C.; Kagan, H. B. Angew. Chem., Int.
Ed. 1998, 37, 2922. (f) Berrisford, D. J .; Bolm, C.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1059. (g) Reetz, M. T.; J aeger,
K.-E. Chem. Eur. J . 2000, 6, 407. (h) J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds. Comprehensive Asymmetric Catalysis; Springer:
New York, 1999.
(5) Feringa, B. L.; de Lange, B. Tetrahedron 1988, 44, 7413.
(6) Moradei, O. M.; Paquette, L. A.; Peschko, C.; Danheiser, R. L.
Org. Synth. 2003, 80, 66.
(7) Feringa, B. L.; de Lange, B.; J ansen, J . F. G. A.; de J ong, J . C.;
Lubben, M.; Faber, W.; Schudde, E. P. Pure Appl. Chem. 1992, 64,
1865.
(8) (a) Kang, F.-A.; Yu, Z.-Y.; Yin, H.-Y.; Yin, C.-L. Tetrahedron:
Asymmetry 1997, 8, 3591. (b) Cornett, B.; Davis, M.; Wu, S.; Nevins,
N.; Snyder, J . P. J . Am. Chem. Soc. 1998, 120, 12145. (c) Mulzer, J .;
Riether, D. Tetrahedron Lett. 1999, 40, 6197.(e) Kang, F.-A.; Yin, C.-
L.; She, S.-W. J . Org. Chem. 1996, 61, 5523.
(3) Blaser, H.-U. Chem Commun. 2003, 293.
(4) Martel, J .; Tessier, J .; Demoute, J .-P. (Roussel-UCLAF) Eur. Pat.
Appl. 23454, 1981.
(9) Krief, A.; Lecomte, Ph.; Demoute, J . P.; Dumont, W. Synthesis
1990, 275.
10.1021/jo030292x CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004
1646
J . Org. Chem. 2004, 69, 1646-1651

Origin of Chiral Induction in Radical Reactions
reactions,11,12 additions of dipole compounds13 and rad-
icals,14-16 tandem or domino reactions,17 cis-hydroxyla-
tions,18 and complexation to metal atoms19 have been
carried out often with complete facial diastereoselectivity.
Photochemical [2 + 2] cycloaddition which occurs at the
excited state of 1 was significantly less diastereoselec-
tive20,21 since the geometry of the excited state of alkoxy-
furanones is significantly different from the ground-state
geometry.22
(5R)-5-l-Menthyloxyfuran-2[5H]-one (1) was easily ob-
tained in dia- and enantiopure form due to the high
crystallinity of this menthol derivative. Many similar
menthyloxy derivatives have been described in the
literature. Menthyloxyfuranone derivatives carrying an
additional alkyl substituent21,23,24 or halogen atoms at the
double bond10,25 have been obtained in enantiopure form.
Sulfonyl or sulfinyl substituents in these positions are
sometimes necessary to enhance the reactivity.26 Menthol
seems to contribute significantly to the high crystallinity
of one diastereomeric acetal. All attempts to replace it
by another enantiopure alcohol were not successful.12,27
In some of these cases, however, the diastereomers could
be separated by chromatography.
For the first time, the present publication reports the
isolation of (5S)-5-l-menthyloxyfuran-2[5H]-one (2). De-
spite numerous applications to asymmetric organic syn-
thesis, only few publications give a deeper insight into
the origin of chiral induction of 1 or en t-1. One major
question which frequently arises deals with the influence
of the menthyloxy substituent, and many alternatives are
proposed. The following study reveals the influence of the
chiral acetal function on one hand and the menthyl
moiety on the other hand, on the diastereoselectivity of
the tandem addition cyclization reaction of 1 and 2 with
tertiary aromatic amines.
Resu lts a n d Discu ssion
(5R)-5-l-Menthyloxyfuran-2[5H]-one (1) was synthe-
sized in two steps (Scheme 1). Photooxygenation of
furfural 328 provided 5-hydroxyfuran-2[5H]-one 4 in high
yield (91%). The reaction was preferentially carried out
in methanol as solvent. During the reaction and when
the solvent was evaporated, care was taken to maintain
the temperature under 35 °C so that to acetalization with
methanol was avoided.29 Acetalization with (-)-menthol
yielded the two diastereomers (5R)- (1) and (5S)-5-l-
menthyloxyfuran-2[5H]-one (2) with a ratio of about 1/1.
When the recrystallization from petroleum ether was
carried out at about 4 °C or at room temperature, only
the (5R)-diastereoisomer 1 was isolated.30 This isomer
was mostly applied to organic synthesis. Especially in the
case when the crystallization is carried out in the
presence of traces of acid, 2 is progressively transformed
into 1 as far as the latter crystallizes.5 In this way, only
one stereoisomer of 5-menthyloxyfuran-2[5H]-one is ob-
tained. However, when the crystallization was performed
from petroleum ether at -28 °C, two forms of crystals
were observed. Small needles possessing a melting point
of 79 °C were isolated as the major product and cor-
respond to structure 1. Aside from this isomer, more
massive crystals could be picked out in gram scale. These
crystals with a melting point of 41 °C possess a size
between 2 mm and 2.5 cm and correspond to structure
2. They have been picked out with tweezers or have been
recovered by passing the crystal mixture through a sieve.
Some characteristic NMR data are also given in the
Supporting Information.
(10) Huang, H.; Chen, Q. Tetrahedron: Asymmetry 1999, 10, 1295.
(11) (a) Feringa, B. L.; de J ong, J . C. J . Org. Chem. 1988, 53, 1125.
(b) Pelter, A.; Ward, R. S.; Qianrong, L.; Pis, J . Tetrahedron: Asym-
metry 1994, 5, 909. (c) Bush, E. J .; J ones, D. W. J . Chem. Soc., Perkin
Trans. 1 1996, 151. (d) J auch, J . Eur. J . Org. Chem. 2001, 473. (e)
Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J .; Gallou, F.;
Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J . Am. Chem.
Soc. 2001, 123, 9021.
(12) de J ong, J . C.; van Bolhuis, F.; Feringa, B. L. Tetrahedron:
Asymmetry 1991, 2, 1247.
(13) (a) Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, R. W. J .;
Feringa, B. L. Tetrahedron: Asymmetry 1994, 5, 607. (b) Cooper, D.
M.; Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J . Tetrahedron
1995, 51, 7791.
(14) (a) Hoffmann, N. Tetrahedron: Asymmetry 1994, 5, 879. (b)
Belokon, Yu. N.; Kochetkow, K. A.; Moskalenko, M. A.; Raevsky, N.
I.; Savel’eva, T. F.; Tararov, V. I.; Churkina, T. D. Russ. Chem. Bull.
1995, 44, 517. (c) Brule´, C.; Hoffmann, N. Tetrahedron Lett. 2002, 43,
69.
(15) (a) Bertrand, S.; Glapski, C.; Hoffmann, N.; Pete, J .-P. Tetra-
hedron Lett. 1999, 40, 3169. (b) Bertrand, S.; Hoffmann, N.; Pete, J .-
P. Tetrahedron Lett. 1999, 40, 3173. (c) Bertrand, S.; Hoffmann, N.;
Pete, J .-P. Eur. J . Org. Chem. 2000, 2227. (d) Marinkovic´, S.; Hoffmann
N. Chem. Commun. 2001, 1576. (e) Marinkovic´, S.; Hoffmann N. Intern.
J . Photoenergy 2003, 5, 175.
(16) Bertrand, S.; Hoffmann, N.; Humbel, S.; Pete, J .-P. J . Org.
Chem. 2000, 65, 8690.
(17) (a) Van Speybroeck, R.; Guo, H.; Van der Eycken, J .; Vander-
walle, M. Tetrahedron 1991, 47, 4675. (b) Pelter, A.; Ward, R. S.; Storer,
N. P. Tetrahedron 1994, 50, 10829. (c) Pelter, A.; Ward, R. S.; Abd-
el-Ghani, A. J . Chem. Soc., Perkin Trans. 1 1996, 1353. (d) Brinksma,
J .; van der Deen, H.; van Oeveren, A.; Feringa, B. L. J . Chem. Soc.,
Perkin Trans. 1 1998, 4159. (e) J auch, J . J . Org. Chem. 2001, 66, 609.
(18) Sundermann, B.; Scharf, H.-D. Tetrahedron: Asymmetry 1996,
7, 1995.
(19) Enders, D.; Schmitz, T.; Raabe, G.; Kru¨ger, C. Acta Crystallogr.
1991, C47, 37.
(20) (a) Hoffmann, N.; Scharf, H.-D.; Runsink, J . Tetrahedron Lett.
1989, 30, 2637. (b) Bertrand, S.; Hoffmann, N.; Pete, J .-P. Tetrahedron
1998, 54, 4873.
(21) Hoffmann, N.; Scharf, H.-D. Liebigs Ann. Chem. 1991, 1273.
(22) (a) Hoffmann, N.; Buschmann, H.; Raabe, G.; Scharf, H.-D.
Tetrahedron 1994, 50, 11167. For a recent study with similar mol-
ecules, see: (b) Albie´s, R.; de March, P.; Figueredo, M.; Font, J .; Fu,
X.; Racamonde, M.; Alvarez-Larena, A.; Piniello, J . F. J . Org. Chem.
2003, 68, 1283.
(23) (a) Ro¨hrig, S.; Hennig, L.; Findeisen, M.; Welzel, P.; Frischmuth,
K.; Marx, A.; Petrowitsch, T.; Koll, P.; Mu¨ller, D.; Mayer-Figgen, H.;
Sheldrick, W. S. Tetrahedron 1998, 54, 3413. (b) Grossmann, G.;
Se´quin, U. Synlett 2001, 278.
(26) (a) de J ong, J . C.; van den Berg, K. J .; van Leusen, A. M.;
Feringa, B. L. Tetrahedron Lett. 1991, 32, 7751. (b) Garc´ıa Ruano, J .
L.; Bercial, F.; Fraile, A.; Mart´ın Castro, A. M.; Mart´ın, M. R.
Tetrahedron: Asymmetry 2000, 11, 4737. (c) Garc´ıa Ruano, J . L.;
Bercial, F.; Gonza´lez, G.; Mart´ın Castro, A. M.; Mart´ın, M. R.
Tetrahedron: Asymmetry 2002, 13, 1993.
(27) (a) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155. (b)
Cui, J .; Du, B.; Chen, Q. Sci. Chin. (Ser. B) 1998, 41, 65. (c) Frischmuth,
K.; Mu¨ller, D.; Welzel, P. Tetrahedron 1998, 54, 3401. (d) Hoffmann,
N. Ph.D. Dissertation, RWTH Aachen, 1992.
(28) (a) Schenck, G. O. Liebigs Ann. Chem. 1953, 584, 156. (b)
Schroeter, S.; Appel, H. R.; Brammer, R.; Schenck, G. O. Liebigs Ann.
Chem. 1966, 697, 42.
(29) Bolz, G.; Wiersdorff, W.-W. (BASF) German Offen. 2111119,
1972.
(24) Gawronski, J . K.; van Oeveren, A.; van der Deen, H.; Leung,
C. W.; Feringa, B. L. J . Org. Chem. 1996, 61, 1513.
(25) (a) Fenske, D.; Merzweiler, K. Z. Naturforsch. 1989, 44b, 879.
(b) Chen, Q. H.; Geng, Z.; Huang, B. Tetrahedron: Asymmetry 1995,
6, 401. (c) Curtius, F. W.; Scharf, H.-D. Tetrahedron: Asymmetry 1996,
7, 2957. (d) Gerlach, K.; Hoffmann, H. M. R.; Wartchow, R. J . Chem.
Soc., Perkin Trans. 1 1998, 3867. (e) Huang, H.; Chen, Q. Tetrahe-
dron: Asymmetry 1998, 9, 4103. (f) Maestro, M. C.; Barquilla, M. C.;
Mart´ın, M. R. Tetrahedron: Asymmetry 1999, 10, 3593.
(30) The diastereoismer en t-1 possessing the S configuration at the
acetal center can be obtained via the same procedure using d-menthol
as chiral substrate.
J . Org. Chem, Vol. 69, No. 5, 2004 1647

Marinkovic´ et al.
SCHEME 2
SCHEME 3. Mech a n ism of th e Ta n d em
Ad d ition -Cycliza tion Rea ction a n d th e Com p etin g
P a r tia l Red u ction of 1 or 2
These observations suggest that the formation of
crystal germs at low temperature is faster for the isomer
1 than for 2. The crystal growth, however, seems to be
faster for 2 than for 1. The crystals of 1 are stable at
room temperature while those of 2 are less stable. After
∼2 months, we observed small needles growing slowly
on the surface of these crystals even when they were
stored at 4 °C. 2 is transformed slowly into 1, which
indicates that the metastability of crystalline 2 is rather
low. Nevertheless, they were sufficiently stable to per-
form studies with this menthyloxyfuranone isomer. Such
crystalline-induced dynamic resolution are well-known,
and some of them have even been applied at industry
scale.3,31-34 It should be mentioned that the crystallization
must be carried out in absence of any trace of acid.
Otherwise, only crystals of 1 are recovered even at low
temperature. Apparently, the acid-catalyzed epimeriza-
tion of 2 is too fast to permit its crystallization.
When diastereoselective reactions with (5R)-5-l-men-
thyloxyfuran-2[5H]-one (1) are studied, the question
frequently arises what is the contribution of the menthyl
group to chiral induction. Having the two stereoisomers
(R)- (1) and (S)-5-l-menthyloxyfuran-2[5H]-one (2) in
hand, we decided to determine the part of chirality
induced by the acetal and that one induced by the
menthyl moiety. According to the concept of double
CHART 1. P r ivileged Con for m a tion s Obta in ed by
NOESY Mea su r em en ts a n d Mod eliza tion
(31) These crystalline-induced dynamic resolutions are also named
asymmetric transformation of second order or second kind while the
corresponding reactions in solution are called asymmetric transforma-
tion of first order or first kind.
(32) (a) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions; J . Wiley & Sons: New York, 1981. (b) Sheldon, R. A.
Chirotechnology; Marcel Dekker: New York, 1993. (c) Chirality in
Industry I; Collins, A. N., Sheldrake, G. N., Crosby, J ., Eds.; J . Wiley
& Sons: Chichester, 1992. (d) Bruggink, A. Chirality in Industry II;
Collins, A. N., Sheldrake, G. N., Crosby, J ., Eds.; J . Wiley & Sons:
Chichester, 1997.
(33) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; J . Wiley & Sons: New York, 1994.
(34) For more recent examples, see: (a) Kosˇmrlj, J .; Weigel, L. O.;
Evans, D. A.; Downey, C. W.; Wu, J . J . Am. Chem. Soc. 2003, 125,
3208. (b) Brands, K. M. J .; Payack, J . F.; Rosen, J . D.; Nelson, T. D.;
Candelario, A.; Huffman, M. A.; Zhao, M. M.; Li, J .; Craig, B.; Song,
Z. J .; Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. P.; Rossen,
K.; Dormer, P. G.; Reamer, R. A.; Welch, C. J .; Mathre, D. J .; Tsou, N.
N.; McNamara, J . M.; Reider, P. J . J . Am. Chem. Soc. 2003, 125, 2129
and references therein.
induction,35 these two elements could constitute a matched
and a mismatched pair in the isomers 1 and 2.36
To examine this hypothesis, we have chosen the
diastereoselective radical tandem addition cyclization
reaction with N,N-dimethylaniline 5. As we have recently
reported in the case of 1, this reaction could be efficiently
carried out under the conditions of photochemical induced
electron transfer using electron-donor-substituted aro-
(36) It should be noted that the concept of double induction was
mainly developed for cases where chiral information is localized on
the two reaction partners. Nevertheless, the concept should be ap-
plicable for cases where the two elements of chiral induction are located
only on one substrate as far as the two corresponding diastereomers
are investigated. For corresponding examples, see: Evans, D. A.; Clark,
J . S.; Metternich, R.; Novack, V. J .; Sheppard, G. S. J . Am. Chem. Soc.
1990, 112, 866.
(35) (a) Guette´, J .-P.; Horeau, A. Bull Soc. Chim. Fr. 1967, 1747.
(b) Horeau, A.; Kagan, H. B.; Vigneron, J . P. Bull. Soc. Chim. Fr. 1968,
3795. (c) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
1648 J . Org. Chem., Vol. 69, No. 5, 2004

Origin of Chiral Induction in Radical Reactions
CHART 2. P r ivileged Con for m a tion s Obta in ed by NOESY Mea su r em en ts a n d Mod eliza tion
matic ketones (e.g., Michler’s ketone) as sensitizer (Scheme
2).16,37 When the reaction was performed with (R)-5-l-
menthyloxyfuran-2[5H]-one (1), the tetrahydroquinoline
derivatives 6a ,b were isolated with a diastereomeric ratio
of 21/1 (91% de). X-ray structure analysis of the major
compound 6a indicated that the radical attack of the
intermediately formed R-aminoalkyl radicals A (Scheme
3) added preferentially anti with respect to the menthyl-
oxy substituent.37 The resulting electrophilic oxoallyl B
radical then added rapidly with the electron rich aromatic
ring. The resulting intermediate C underwent rearoma-
tization to yield the final products 6a ,b. This oxidation
step was accompanied with the partial reduction of 1
which lead to the formation of 8. We completely sup-
pressed this side reaction by adding ketones such as
acetone to the reaction mixture (for mechanistic details
see ref 16). Now, we have carried out the reaction with
(S)-5-l-menthyloxyfuran-2[5H]-one (2) under the same
conditions. Once again, the radical attack occurred
preferentially anti with respect to the menthyloxy sub-
stituent. However, the major tetrahydroquinoline deriva-
tive 7a was only obtained in a ratio of about 3:1 (53%
de) with the isomer 7b resulting from the opposite radical
attack. Furthermore, the yield of tetrahydroquinolines
was lower and the side product 8 resulting from the
partial reduction of 2 was also obtained (compare Scheme
3).
To explain these results, we have carried out a con-
formational analysis of both diastereoisomers 1 and 2 by
NMR. Using the quantitative NOESY technique, we were
able to determine interatomic distances around the acetal
function. On the basis of these values, a modeling of 1
and 2 was carried out using MM3 calculations and Monte
Carlo type of conformational analysis. One thousand
starting geometries with randomly drawn diedral angles
were submitted to geometry optimization. The preferen-
tial conformations are shown in Chart 1. In both cases,
one face of the flat furanone ring is sterically hindered
by the chiral acetal function. Nevertheless, the olefinic
moiety remains free for attack of a reaction partner in
the â-position. The main difference between the two
diastereoisomers results from the orientation of the
menthyl moiety. In the case of 1, the isopropyl substitu-
ent reaches into the encumbered face, while in the
preferential conformation of 2, only a CH2 group of the
menthyl ring is placed in the hindered face. The methyl
group in position 5 is directed in a concave manner and
does not have a significant influence on the stereoselec-
tion.
To check whether these steric effects are really the
main cause of the stereoselectivity, we have performed
the same kind of structural analysis on the main products
6a and 7a of the tandem addition cyclization reaction
(Scheme 2). The results are shown in Chart 2. In 6a as
well as in 7a the orientations of the menthyl substituent
in the privileged conformations are almost identical with
those ones of the in the privileged conformations of the
corresponding substrates 1 and 2. In the case 6a , two
conformations of almost equal energy were found from
modeling which was guided by the atom distances
obtained from NOESY measurements. The differences
result from the orientation of the CH2 group of the
tetrahydroquinoline moiety. In structure 6a , it is turned
anti with respect to the acetal function while in structure
6a ′ it is turned in a syn position. As a consequence, the
tetrahydrofuranone possesses different envelope confor-
mations. However, these differences have no significant
influence on the orientation of the mentyl subsituent.
X-ray structure analysis of compounds 6a (see ref 37)
and 7a could be carried out, and we wondered whether
the orientations of the menthyl substituent in the crystal
resembled those ones in solution. The results of these
analysis are shown in the supporting material. The scalar
properties of the diastereoisomers are mainly determined
by the relative configuration near the chiral centers of
the acetal function of the furanone moieties and the C1′
of the mentyl substituent. The characteristic param-
eters: distances H5-H1′, H5-H6′eq and H5-H7′ and
the torsion angle of H5-C5-C1′-H1′ are given in the
Supporting Information. There are very similar orienta-
tions of the menthyloxy substituent of 1 in solution and
the corresponding products 6a (or 6a ′) in solution and in
the crystal. The same observation is made for 2 and 7a
in solution and the crystal. However, significant differ-
ences in the orientation of the menthyloxy substituent
are observed for structures resulting from the diastereo-
mer 1 and structures resulting from 2. Due to the
similarity of conformations in the substrates and the
corresponding products, we suppose that very similar
conformers should exist in the transition state of the
addition of the R-aminoalkyl radical A to 1 or 2 (Scheme
3) leading to the intermediate B. A modification of the
(37) Bertrand, S.; Hoffmann, N.; Pete, J . P.; Bulach, V. Chem.
Commun. 1999, 2291.
J . Org. Chem, Vol. 69, No. 5, 2004 1649

Marinkovic´ et al.
SCHEME 4
one (en t-1)) can easily be isolated in pure form by
crystallization as described in the literature. By applying
particular crystallization conditions, we have also iso-
lated the diastereomer (5S)-5-l-menthyloxyfuran-2[5H]-
one (2) in pure form. In contrast to the expectation that
chiral induction only occurs by the acetal center, we
observed significantly different diastereoselectivities in
the radical reactions of 1 or 2 with the amine 5. A
conformational analysis of the substrates 1 and 2 as well
as of the major products 6a and 7a of the radical reaction
indicated that the diastereoselectivity of the investigated
reaction can be explained by the privileged conformations
of 1 and 2 in which the facial hindrance is significantly
different. Concerning two elements of chiral induction,
it is concluded that the acetal function contribute mainly
to the chiral induction (∼70%) while the menthyl moiety
contributes to a minor degree (∼30%).
stereoselectivity by an eventual reversibility of this step
should be negligible since intermediate B reacts rapidly
via intramolecular addition of the electrophilic oxoallyl
radical to the electron- rich aniline moiety.38,39 The
difference of stereoselectivity in the radical tandem
addition cyclization reaction of N,N-dimethylaniline 5
with the diastereoisomers 1 and 2 of menthyloxyfuran-
2[5H]-one may be explained essentially by the steric
hindrance in two different conformations. In this context,
the observed stereoselectivity do not fit with the assump-
tions made for the Curtin-Hammett principle.33,40
As mentioned above, the chirality is induced by two
elements, the acetal center and the menthyl substituent.
In the context of double induction,35 these two elements
constitute a matched pair in the case of 1 and a
mismatched pair in the case of 2. The dominant factor is
the acetal function since the attack of the R-aminoalkyl
radical occurs preferentially anti with respect to the
menthyloxy substituent. A minor part of the chirality is
induced by the menthyl moiety. If we consider that the
observed stereoselectivity results from the sum of both
effects according to the concept of double induction, about
70% of the chiral induction results from the acetal and
30% from the menthyl moiety (based on the correspond-
ing ∆∆Gq values which are obtained according to refs 33,
35, 40).
Exp er im en ta l Section
(5R)-5-l-Men t h yloxyfu r a n -2[5H]-on e (1) a n d (5S)-5-l-
Men th yloxyfu r a n -2[5H]-on e (2). A solution of 5-hydroxy-
furan-2[5H]-one (4) (110 g), (-)-menthol (17 2 g), and catalytic
amounts of p-touluenesulfonic acid in toluene (1 L) were heated
under reflux with
a Dean-Stark apparatus until water
separation ceased (after about 10 h). The reaction solution was
washed with a saturated solution of NaHCO3 and water. The
organic phase was separated and dried with MgSO4. After
evaporation of the toluene, the residue was crystallized from
petroleum ether (500 mL) at -28 °C. The crystals were washed
with a small amount of cooled petroleum ether. The large
crystals of 2 were picked out with tweezers. Smaller crystals
of 2 were separated by passing the crystal mixture through a
sieve. The needle formed crystals were recrystallized from
petroleum ether. Yield of 2: 14.2 g (5%). Yield of 1: 107.1 g
(41%). Further fractions of 1 were recovered by the ordinary
crystallization process at 4 °C.
1: mp 79 °C; [R]24 ) -135.4, [R]24 ) -140.5, [R]24
)
D
578
546
-159.1, [R]24436 ) -269.8, [R]24365 ) -428.5 (c ) 0.948, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.17 (dd, J ) 1.1, 5.7 Hz, 1H),
6.21 (dd, J ) 1.1, 5.7 Hz, 1H), 6.09 (t, J ) 1.1 Hz, 1H), 3.66
(dt, J ) 4.5, 10.5 Hz, 1H), 2.16 (m, 1H), 2.12 (dsep, J ) 2.5,
7.0 Hz, 1H), 1.67 (m, 2H), 1.41 (m, 1H), 1.26 (ddt, J ) 13.2,
10.5, 2.5 Hz, 1H), 0.99 (m, 1H), 0.96 (m, 1H), 0.95 (d, J ) 6.5
Hz, 3H), 0.88 (d, J ) 7 Hz, 3H), 0.83 (m, 1H), 0.80 (d, J ) 7
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ ) 170.8, 150.9, 124.8,
100.4, 79.1, 47.7, 40.3, 34.1, 31.4, 25.3, 23.1, 22.2, 20.8, 15.7.
Anal. Calcd for C14H22O3 (238.3): C, 70.59; H, 9.24. Found:
C, 70.33; H, 9.59.
To demonstrate an application in asymmetric synthe-
sis, the major isomers 6a and 7a were transformed into
the corresponding enantiomeric tetrahydroquinolines 9
and en t-9 (Scheme 4). The chiral auxiliary is removed
via NaBH4 reduction. The opposite optical rotatory power
of the products gave further support for the configura-
tions of 6a and 7a .
2: mp 41 °C; [R]24 ) -19.6, [R]25
) -20.2, [R]25
)
D
578
546
-22.9, [R]25
) -35.6, [R]25
) -41.1 (c ) 0.950, CHCl3);
436
365
1H NMR (500 MHz, CDCl3) δ 7.19 (dd, J ) 1.0, 5.7 Hz, 1H),
6.18 (dd, J ) 1.0, 5.7 Hz, 1H), 5.94 (s, 1H), 3.50 (dt, J ) 4.4,
10.5 Hz, 1H), 2.23 (m, 1H), 2.10 (dsep, J ) 2.5, 7.0 Hz, 1H),
1.63 (m, 2H), 1.38 (m, 1H), 1.27 (ddt, J ) 13.3, 10.5, 2.5 Hz,
1H), 1.04 (dd, J ) 10.5, 12.2 Hz, 1H), 0.98 (m, 1H), 0.90 (d, J
) 7 Hz, 6H), 0.82 (m, 1H), 0.79 (d, J ) 7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.6, 150.3, 124.6, 104.5, 82.9, 48.0, 42.4,
34.0, 31.5, 25.6, 23.1, 22.1, 20.8, 16.2; IR (KBr) ν ) 3496, 3088,
2955, 2924, 2867, 1795, 1752, 1456, 1134, 1011, 899 cm-1; MS
(EI) m/z 239 [M+ + 1] (40), 221 (6), 153 (21), 139 (100), 123
(38), 109 (19). Anal. Calcd for C14H22O3 (238.3): C, 70.59; H,
9.24. Found: C, 70.27; H, 9.63.
Con clu sion
In summary, the (5R)-5-l-menthyloxyfuran-2[5H]-one
(1) diastereoisomer (or (5S)-5-d-menthyloxyfuran-2[5H]-
(38) For a discussion of chiral induction in multistep reactions, see:
(a) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew.
Chem., Int. Ed. Engl. 1991, 30, 477. (b) Cainelli, G.; Giacomini, D.;
Galletti, P. Chem. Commun. 1999, 567.
(39) For the contribution of polar effects in radical reactions, see:
(a) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340. (b)
Tedder, J . M. Angew. Chem., Int. Ed. Engl. 1982, 21, 401. (c) Giese, B.
Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (c) Roberts, B. Chem. Soc.
Rev. 1999, 28, 25.
Tetr a h yd r oqu in olin e Der iva tives (6a ,b). These products
were obtained as previously described.16
Tetr a h yd r oqu in olin e Der iva tives (7a ,b). A solution of
(5S)-5-l-menthyloxyfuran-2[5H]-one (2) (420 mg), N,N-dimethyl-
aniline, 4,4′-bis(dimethylamino)benzophenone (40 mg), and
acetone (2 mL) in acetonitrile (30 mL) was placed in Pyrex
tubes (1.7 cm diameter). After being degassed with argon, the
(40) Nasipuri, D. Stereochemistry of Organic Compounds; J . Wiley
& Sons: New York, 1991.
1650 J . Org. Chem., Vol. 69, No. 5, 2004

Origin of Chiral Induction in Radical Reactions
solution was irradiated for 8 h in a Rayonet apparatus The
solvent was evaporated, and the residue was subjected to flash
chromatography (ethyl acetate/petroleum ether). A fraction of
180 mg of pure 7a was isolated. Another fraction of 98 mg
contained 7a and 7b in ratio of 1/2. (Yield of 7a ,b: 44%). The
diastereoselectivity was also determined from unseparated
grateful to Etienne Derat (UMR 6519, Mode´lisation et
Re´activite´ Chimique) for his help with format transfor-
mations of graphical files. This work was funded by the
CNRS and the Deutsche Forschungsgemeinschaft in the
context of a French German bilateral research project.
mixture. Yield of 8: 100 mg (24%). 7a : mp 147 °C; [R]24
)
D
+91.3, [R]25
) +94.1, [R]25
) +104.3, [R]25
) +138.1,
578
546
436
[R]25 ) +29.2 (c ) 1.012, CH2Cl2).
Su p p or tin g In for m a tion Ava ila ble: General methods of
365
1
the Experimental Section; synthesis of 4; parts of the H and
Tetr a h yd r oqu in olin e Der iva tives (9 a n d en t-9). Prepa-
ration and characterization are given in the Supporting
Information.
Cr ysta l Str u ctu r e Ch a r a cter iza tion of 7a . The crystal
structure of 6a has already been reported.37 Data for 7a are
given in the Supporting Information and deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-212034 (excluding structure factors).
13C NMR spectra of compounds 1 and 2 and a table with
characteristic chemical shifts; spectroscopic data of 7a ,b and
8; X-ray experimental data for compound 7a ; a Table with
characteristic structural parameters obtained from NMR data
1
or X-ray structure analysis from 1, 2, 6a , and 7a ; H and 13C
NMR spectra of compound 8; ORTEP representations of X-ray
structures of 7a and 9a . This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. S.M. thanks the Ministe`re de la
Recherche for a doctoral fellowship. We are particularly
J O030292X
J . Org. Chem, Vol. 69, No. 5, 2004 1651